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Transforming growth factor beta-mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element.

Publication ,  Journal Article
Frederick, JP; Liberati, NT; Waddell, DS; Shi, Y; Wang, X-F
Published in: Mol Cell Biol
March 2004

Smad proteins are the most well-characterized intracellular effectors of the transforming growth factor beta (TGF-beta) signal. The ability of the Smads to act as transcriptional activators via TGF-beta-induced recruitment to Smad binding elements (SBE) within the promoters of TGF-beta target genes has been firmly established. However, the elucidation of the molecular mechanisms involved in TGF-beta-mediated transcriptional repression are only recently being uncovered. The proto-oncogene c-myc is repressed by TGF-beta, and this repression is required for the manifestation of the TGF-beta cytostatic program in specific cell types. We have shown that Smad3 is required for both TGF-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes. The transcriptional repression of c-myc is dependent on direct Smad3 binding to a novel Smad binding site, termed a repressive Smad binding element (RSBE), within the TGF-beta inhibitory element (TIE) of the c-myc promoter. The c-myc TIE is a composite element, comprised of an overlapping RSBE and a consensus E2F site, that is capable of binding at least Smad3, Smad4, E2F-4, and p107. The RSBE is distinct from the previously defined SBE and may partially dictate, in conjunction with the promoter context of the overlapping E2F site, whether the Smad3-containing complex actively represses, as opposed to transactivates, the c-myc promoter.

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Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

March 2004

Volume

24

Issue

6

Start / End Page

2546 / 2559

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Transcription Factors
  • Trans-Activators
  • Smad3 Protein
  • Recombinant Proteins
  • RNA, Messenger
  • Proto-Oncogene Mas
  • Promoter Regions, Genetic
  • Mutagenesis
  • Mice, Knockout
 

Citation

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Frederick, J. P., Liberati, N. T., Waddell, D. S., Shi, Y., & Wang, X.-F. (2004). Transforming growth factor beta-mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element. Mol Cell Biol, 24(6), 2546–2559. https://doi.org/10.1128/MCB.24.6.2546-2559.2004
Frederick, Joshua P., Nicole T. Liberati, David S. Waddell, Yigong Shi, and Xiao-Fan Wang. “Transforming growth factor beta-mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element.Mol Cell Biol 24, no. 6 (March 2004): 2546–59. https://doi.org/10.1128/MCB.24.6.2546-2559.2004.
Frederick, Joshua P., et al. “Transforming growth factor beta-mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element.Mol Cell Biol, vol. 24, no. 6, Mar. 2004, pp. 2546–59. Pubmed, doi:10.1128/MCB.24.6.2546-2559.2004.

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

March 2004

Volume

24

Issue

6

Start / End Page

2546 / 2559

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta
  • Transcription Factors
  • Trans-Activators
  • Smad3 Protein
  • Recombinant Proteins
  • RNA, Messenger
  • Proto-Oncogene Mas
  • Promoter Regions, Genetic
  • Mutagenesis
  • Mice, Knockout